The present invention relates to new compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to inhibit NAALADase enzyme activity, detecting diseases where NAALADase levels are altered, inhibit angiogenesis, effect neuronal activity, and treat glutamate abnormalities, neuropathy, pain, prostate diseases, cancers, TGF-xcex2 abnormalities, compulsive disorders, and glaucoma.
The NAALADase enzyme, also known as prostate specific membrane antigen (xe2x80x9cPSMxe2x80x9d or xe2x80x9cPSMAxe2x80x9d) and human glutamate carboxypeptidase II (xe2x80x9cGCP IIxe2x80x9d), catalyzes the hydrolysis of the neuropeptide N-acetyl-aspartyl-glutamate (xe2x80x9cNAAGxe2x80x9d) to N-acetyl-aspartate (xe2x80x9cNAAxe2x80x9d) and glutamate. Based upon amino acid sequence homology, NAALADase has been assigned to the M28 family of peptidases.
Studies suggest NAALADase inhibitors may be effective in treating ischemia, spinal cord injury, demyelinating diseases, Parkinson""s disease, Amyotrophic Lateral Sclerosis (xe2x80x9cALSxe2x80x9d), alcohol dependence, nicotine dependence, cocaine dependence, cancer, diabetic neuropathy, pain and schizophrenia, and in inhibiting angiogenesis. In view of their broad range of potential applications, a need exists for new NAALADase inhibitors and pharmaceutical compositions comprising such compounds.
Specifically, the present invention relates to a compound of formula I 
or a pharmaceutically acceptable equivalent, wherein:
X is xe2x80x94Wxe2x80x94Z;
W is a bond or a linking group;
Z is a terminal group; and
Y is xe2x80x94COOH oriented meta or para relative to C-1.
Additionally, the present invention relates to a method for inhibiting NAALADase enzyme activity, treating a glutamate abnormality, effecting a neuronal activity (e.g., treating peripheral neuropathy or neuropathic pain), treating a prostate disease, treating cancer, inhibiting angiogenesis, or effecting a TGF-xcex2 activity, comprising administering to a mammal in need of such inhibition, treatment, or effect, an effective amount of a compound of formula I, as described above.
The present invention further relates to method for detecting a disease, disorder, or condition where NAALADase levels are altered, comprising:
(i) contacting a sample of bodily tissue or fluid with a compound of formula I, as defined above, wherein said compound binds to any NAALADase in said sample; and
(ii) measuring the amount of any NAALADase bound to said sample, wherein the amount of NAALADase is diagnostic for said disease, disorder or condition.
The present invention further relates to a method for detecting a disease, disorder or condition where NAALADase levels are altered in an animal or a mammal, comprising:
(i) labeling a compound of formula I, as defined above, with an imaging reagent;
(ii) administering to said animal or mammal an effective amount of the labeled compound;
(iii) allowing said labeled compound to localize and bind to NAALADase present in said animal or mammal; and
(iv) measuring the amount of NAALADase bound to said labeled compound, wherein the amount of NAALADase is diagnostic for said disease, disorder or condition.
The present invention further relates to a diagnostic kit for detecting a disease, disorder or condition where NAALADase levels are altered, comprising a compound of formula I, as defined above, labeled with a marker.
The invention further relates to a pharmaceutical composition comprising:
(i) an effective amount of a compound of formula I or a pharmaceutically acceptable equivalent; and
(ii) a pharmaceutically acceptable carrier.